Facile synthesis of 4-quinolone derivatives via one-pot cascade reaction under transition-metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2015.04.060

A practical and efficient strategy has been described for the preparation of 4-quinolone derivatives. Using commercially available diethyl acetylenedicarboxylate and aromatic amines as starting materials, the synthetic protocol has been achieved and affor

Full text of DOI:10.1016/j.tetlet.2015.04.060

Accepted Manuscript
Facile synthesis of 4-quinolone derivatives via one-pot cascade reaction under
transition-metal-free conditons
Chao Huang, Jia-Hui Guo, Huang-Mei Fu, Ming-Long Yuan, Li-Juan Yang
PII:
S0040-4039(15)00697-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.04.060
TETL 46199
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 February 2015
12 April 2015
16 April 2015
Please cite this article as: Huang, C., Guo, J-H., Fu, H-M., Yuan, M-L., Yang, L-J., Facile synthesis of 4-quinolone
derivatives via one-pot cascade reaction under transition-metal-free conditons, Tetrahedron Letters (2015), doi:
http://dx.doi.org/10.1016/j.tetlet.2015.04.060
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Graphical Abstract
Facile synthesis of 4-quinolone derivatives via one-
pot cascade reaction under transition-metal-free
conditons
Chao Huang a,b, ∗, Jia-Hui Guoa, Huang-Mei Fua, Ming-Long Yuan a,b, Li-Juan Yang a,b

1
Tetrahedron Letters
journal homepage: www.els evier.com
Facile synthesis of 4-quinolone derivatives via one-pot cascade reaction under
transition-metal-free conditons
Chao Huang a,b,∗, Jia-Hui Guo a, Huang-Mei Fu a, Ming-Long Yuan a,b, and Li-Juan Yang a,b
aKey Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming,
650500, China
bEngineering Research Center of Biopolymer Functional Materials of Yunnan, Yunnan Minzu University, Kunming, 650500, China
ARTICLE INFO
ABSTRACT
Article history:
Received
A practical and efficient strategy has been described for the preparation of 4-quinolone
derivatives. Using commercially available diethyl acetylenedicarboxylate and aromatic amines
as starting materials, the synthetic protocol has been achieved and afforded the product via
hydroamination at room temperature followed by PPA-catalyzed intramolecular ring closure.
The products can be easily obtained in high yields. Conditions and mechanism of the reaction
have also been investigated. This protocol is environmentally friendly and transition-metal-free,
with advantages including short reaction time, convenient operation and mild reaction
conditions.
Received in revised form
Accepted
Available online
Keywords:
Quinolone
Transition-metal-free
One pot
Hydroamination
Cascade reaction
2015 Elsevier Ltd. All rights reserved.
4-Quinolone is an important nitrogen-containing heterocycle in
organic synthesis and medicinal chemistry.1 Specifically, 4-
quinolone is a commonly found core structure in the family of
antimicrobial agent such as ofloxacin, norfloxacin,2 etc (Figure
1). Antibacterial drugs containing quinolone moiety gained
tremendous importance of clinical application for their properties
of broad-spectrum bioactivities, potent pharmacokinetics and
unique action mechanism.3 The development and transformation
of these compounds has more than 60 years of history,4
particularly in recent years, confronting with the arising of drug
resistance,5 antibacterial drugs containing the structure of
quinolone has been one of the areas of current research interest.6
On the other hand, the new discovery of significant biological
applications such as, antidiabetic, anticancer and antiviral
activities make the development of synthetic methodology to
access quinolone compounds continually warranted.7 Moreover,
methods for the efficient assemble of the 4-quinolone skeletons
are under-developed.8
reduction in pollution.11 Stimulated by our prior work,12 we have
been interested in method development for the assembly of 4-
quinolone compounds with structural diversity by eco-friendly
route. Traditional process synthetic routes for quinolones, the
Conrad-Limpach and Gould-Jacobs cyclizations were the most
frequently employed. They often carried out in several steps,
time-consuming, with metal catalysts, or strong acids at high
temperature.13 The harsh reaction conditions made synthesis and
isolation of pure products difficult and resulted in low to
moderate yields. Thus, the attention and effort of chemists shift
to develop new methodologies following green chemistry
principles without further complicated and time-consuming
purification process and toxic reagents or solvents.14
O
O
F
CO2H
F
CO2H
HN
N
N
N
N
N
O
Ofloxacin
Norfloxacin
O
Currently, cascade reaction is used as a powerful strategy for
the generation of small molecules with privileged scaffolds using
diversity-oriented synthesis.9 Usually, several bonds can be
formed in a one-pot procedure and complex organic moleculars
can be created.10 One-pot cascade reactions by virtue of their
convergence, elegance, and highly step-economy are particularly
appealing in the context of rapid target-oriented synthesis. These
reactions fall under the fold of green chemistry, as they obviate
the isolation and purification of intermediates leading to
O
R
N
COOEt
N
H
H
4-Quinolone subunit
Figure 1. Selected bioactive compounds with 4-quinolone
subunits and target molecule.
———
∗ Corresponding author. Tel.: +86 871 65910017; fax: +86 871 65910017; e-mail: huang.chao@hotmail.com

2
Tetrahedron Letters
Table 1. Optimization of the reaction conditionsa
Muti-step methods
R
R
O
NH2
Hal
Intermediates
N
H
COOR
EntryCatalystb
Solvent
Solvent-free
Acetone
THF
Temp.c 1a: 2d Time (h)e Yield (%)f
Ref. 1 and 17
Materials
1
2
3
4
5
6
7
8
9
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
rt
rt
rt
rt
1: 1.5
1: 1.5
1
2
15
11
13
11
10
22
25
6
Our approach:
O
1: 1.5
2
COOEt
Base
DCM
1: 1.5
2
R1
+
R2
R1
N
H
Cascade
reaction
One-pot method
Methylbenzene rt
1: 1.5
2
N
R2
COOEt
COOEt
Solvent-free
Solvent-free
90 oC
1: 1.5
1
rt-90 oC 1: 1.5
rt-230 oC 1: 1.5
rt-90 oC 1: 1.5
rt-90 oC 1:1
rt-90 oC 1:2
rt-90 oC 2:1
2
Scheme 1. Strategies for the synthesis of 4-quinolone-2-
carboxylates.
Diphenyl ether Solvent-free
2
PPA
Solvent-free
Solvent-free
Solvent-free
Solvent-free
1.5
1.5
1.5
1.5
72
63
73
70
10 PPA
11 PPA
12 PPA
We designed a protocol for the construction of 4-quinolone-2-
carboxylates via a cascade reaction between commercially
available aromatic amines 1 and diethyl acetylenedicarboxylate 2
(Scheme 1). We found that amines with dimethyl
acetylenedicarboxylate can be used to prepared enamine
substrates,15 which can easy build 4-quinolone-2-carboxylate
construction by the Eaton’s reagent,16 but the multi-step, various
reagents and catalyst-needed process limited its application.17 So
we report a new green strategy for the construction of 4-
quinolone-2-carboxylates via an efficient cascade reaction under
transition-metal-free conditions, with simple starting materials
and mild reaction conditions. The simple post-processing steps
illustrated the important academic value and promising
application prospect. Moreover, the mechanism through which
the solvent-free hydroamination at room temperature and then the
intramolecular Friedel-Crafts reaction has been investigated by
experiments, which verified one practical and efficient alternative
strategy to construct 4-quinolone compounds.
a The reaction was carried out using 1a and 2 in the indicated solvent (1 mL)
in a dry Schlenk tube.
b The catalysts were added after 1a completely consumed (10 min).
c Temperature was adjusted to different catalysts.
d The mole ratio of 1a and 2.
e The total reaction time.
f Isolated yields.
Encouraged by above results, a range of substituted aromatic
amines were employed to further study the scope of the protocol
with mild conditions. A variety of quinolones derivatives have
been obtained from diethyl acetylenedicarboxylate and primary
amines or secondary amines by the identical protocol as
illustrated in Table 2. They provided good to high yield of 4-
quinolone compounds 3, and all of the products 3a-3q were
characterized by IR, H NMR, 13C NMR and the high resolution
mass spectrometry (HRMS).18
1
At first, we studied the reaction between the aniline 1a and the
diethyl acetylenedicarboxylate 2. Under stirring, two materials
could quickly react in solvent-free condition at room-temperature.
However, the 4-quinolone molecule cannot be judged by 1H
NMR analysis. Then we added several catalysts to the reaction
mixture after materials completely consumed, tried to get the 4-
quinolone in one pot. And we found the concentrated sulfuric
acids could enable the reaction mixture to transform 4-quinolone-
2-carboxylate.
An interesting electron density effect of aromatic amines was
observed in this reaction, with the yields being increased as the
electron density of nitrogen atom increased (Table 2, entries 1, 11,
16 and 17). Notably, primary amines bearing electron-
withdrawing group required longer reation time than those
containing electron-donating group (entries 2-5 vs 6-10). Similar
to primary amines, alkyl group of secondary amines, the presence
of which increased the electron density on nitrogen atom,
promoted the transformation, whereas the aromatic group exerted
an adverse effect (entries 11 and 16 vs 17). And the effect of the
steric hindrance and electron density of diphenylamine and
benzylamine fail in affording any product (entries 18, 19). The
good regioselectivity reaction can also be found in meta-
substituted primary amines 1d (entry 4), but poor regioselectivity
in meta-substituted secondary amine 1n (entries 14 and 15).
These results indicated that the electron density effect of
aromatic amines played an important role in the proposed
synthetic strategy.
Next, the aniline 1a and the diethyl acetylenedicarboxylate 2
were treated to optimize the reaction conditions (Table 1). The
reaction could also proceed in different solvents at room
temperature (Table 1, entries 2-5), but no better yields we had
met. In the elevated temperature treatment, the target product was
obtained with higher yields under solvent-free condition (Table 1,
entries 6-7). Other catalysts were screened, and we found
polyphosphoric acid (PPA) is superior to concentrated sulfuric
acids and diphenyl ether (Table 1, entries 7-9). Moreover, the
optimal ratio mole of the materials was 1: 1.5 (Table 1, entries 9-
12). Thus, we defined the reaction of the phenol 1a with 1.5
equiv of the diethyl acetylenedicarboxylate 2 catalyzed by PPA
under transition-metal-free condition from room-temperature to
90 oC as the standard reaction conditions (Table 1, entry 9).

3
Table 2. Construction of 4-quinolone derivatives
Entry
1
1
3
Reaction Time (h)
1.5
Yielda (%)
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
72
2
3
1
75
77
84
90
71
72
72
57
62
1
4
1
5
1
6
1.5
1.5
1.5
1.5
1.5
7
1g
1h
1i
3g
3h
3i
8
9
10
1j
3j
11
1k
3k
1
85

4
Entry
Tetrahedron Letters
3
1
Reaction Time (h)
1.5
Yielda (%)
12
13
14
15
1l
3l
70
1m
1n
1n
3m
3n
3o
1
1
1
90
68 b
30b
16
17
1o
1p
3p
3q
1
1
94
97
18
19
1q
1r
Complex
Complex
a Isolated overall yield for two steps.
b Two products in one reaction.
A plausible rationalization for the formation of the desired
product 3 is depicted in Scheme 2. As an activated non-terminal
alkyne, the lack of electron on the acetylene bond facilitated the
hydroamination reaction of diethyl acetylenedicarboxylate with
aromatic amine, affording the intermediate 4. Followingly, the
intramolecular Friedel-Crafts reaction of 4 furnished the product
3 with PPA as catalyst.19 Due to the effect of electron density and
steric hindrance of nitrogen atom, the structure of aromatic amine
had a significant influence in the protocol.
To understand the mechanism of the cascade reaction process,
ethyl 4-oxo-1,4-dihydroquinoline-2-carboxylate 3a prepared by
multi-step method was used instead of one pot protocol to
authenticate mechanism (Scheme 3). We found that the
intermediate 4a was easy to obtain from aniline to diethyl
acetylenedicarboxylate in a high yield of 83% without any
classical solvent at room temperature. Further investigation
implied that the target 4-quinolone 3a was come from 4a, which
was supported by the case that the cascade reaction through
nucleophilic addition and Friedel-Crafts reaction. These results
also suggest that the cascade reaction is an effective method.
Scheme 3. Two-step synthesis of ethyl 4-oxo-1,4-
dihydroquinoline-2-carboxylate 3a.
Scheme 2. Plausible mechanistic pathway for the formation of 4-
quinolones 3.

5
Med. Chem. Lett. 2013, 23, 2399; (d) Huang, C.; Yan, S. J.;
In summary, a variety of 4-quinolone derivatives have been
quickly synthesized from diethyl acetylenedicarboxylate and
aromatic amines by an efficient and practical protocol with mild
reaction conditions. This method has been achieved without any
classical solvent and simply process afforded the desired product
in good to high yield. The result provided reference for the
syntheses of drugs containing quinolone moiety, also supplied a
basis for the further synthetic methodology research of
heterocycles compounds. Our further investigation into the
application of the strategy in the formation of quinolone
heterocyclic compounds and quinolone drug are currently
ongoing.
Zeng, X. H.; Dai, X. Y.; Zhang, Y.; Qing, C.; Lin, J. Eur. J. Med.
Chem. 2011, 46, 1172; (e) Huang, C.; Yan, S. J.; Li, Y. M.;
Huang, R.; Lin, J. Bioorg. Med. Chem. Lett. 2010, 20, 4665; (f)
Yan, S. J.; Huang, C.; Zeng, X. H.; Huang, R.; Lin, J. Bioorg. Med.
Chem. Lett. 2010, 20, 48; (g) Yan, S. J.; Huang, C.; Su, C. X.; Ni,
Y. F.; Lin, J. J. Comb. Chem. 2010, 12, 91.
13. (a) A. A. Boteva, O. P. K. Chem Heterocycl Comp 2009, 45, 757;
(b) Pasquini, S.; Botta, L.; Scincraro, T.; Mugnaini, C.; Ligresti,
A.; Palazzo, E.; Maione, S.; Di Marzo, V.; Corelli, F. J Med Chem
2008, 51, 5075.
14. Cernuchova, P.; Vo-Thanh, G.; Milata, V.; Loupy, A.
Heterocycles 2004, 64, 177.
15. Choudhary, G.; Peddinti, R. K. Green. Chem. 2011, 13, 3290.
16. Zewge, D.; Chen, C. Y.; Deer, C.; Dormer, P. G.; Hughes, D. L. J.
Org. Chem. 2007, 72, 4276.
Acknowledgments
17. a) Pandey, A. K.; Sharma, R.; Shivahare, R.; Arora, A.; Rastogi,
N.; Gupta, S.; Chauhan, P. M. S. J. Org. Chem. 2013, 78, 1534; b)
Borza, I.; Kolok, S.; Galgóczy, K.; Gere, A.; Horváth, C.; Farkas,
S.; Greiner, I.; Domány, G. Bioorgan. Med. Chem. Lett. 2007, 17,
406; c) Mazzoni, O.; Esposito, G.; Diurno, M. V.; Brancaccio, D.;
Carotenuto, A.; Grieco, P.; Novellino, E.; Filippelli, W. Arch.
Pharm. Chem. Life Sci. 2010, 10, 561; d) Coltman, S. C. W.;
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5323.
This work was supported by the NSFCs (Nos. 21202142) and
the Key Project of Chinese Ministry of Education (No. 212161),
Start-up funds of Yunnan Minzu University. We thank the Key
Laboratory of Resource Clean Conversion in Ethnic Regions，
Education Department of Yunnan and the Joint Research Centre
for International Cross-border Ethnic Regions Biomass Clean
Utilization in Yunnan (Yunnan Minzu University).
18. General procedure: A mixture of aromatic amines 1 (1.0 mmol)
and diethyl acetylenedicarboxylate 2 (1.5 mmol) were stirred at
room temperature, and the reaction was observed as indicated by
TLC. After completion of the reaction, the reaction mixture was
dissolved in 2 mL of PPA followed by temperature rising to 90
°C. The reaction time was shown in Table 2 was performed. After
the end of the reaction, the reaction mixture was cooled and
disposed in 10 mL of water, and then the crude product was
obtained after filtration. The crude mixture was purified by
column chromatography on silica gel to afford pure products 3.
Spectroscopic data for selected compounds:
References and notes
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Ethyl 4-oxo-1,4-dihydroquinoline-2-carboxylate (3a): yield 72%;
white solid; mp 211–212 C (Ref. 8d 210–211 oC); IR (KBr) (νmax
o
,
cm-1) 3408, 3085, 1735, 1614, 1565, 1518, 1438, 1269, 1074, 861,
746 cm ; 1H NMR (400 MHz, CD3Cl): δ 8.34 (1H, s), 7.68-7.64
-1
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(1H, m), 7.39-7.39 (1H, m), 7.37-7.35 (1H, m), 7.26 (1H, s), 7.02
(1H, s), 4.48-4.43 (2H, q, J = 8.0 Hz), 1.43-1.39 (3H, m); 13C
NMR (100 MHz, CD3Cl): δ 179.7, 162.9, 139.3, 136.8, 133.1,
126.2, 124.6, 118.4, 111.5, 63.3, 29.7, 14.1; HRMS (ESI-TOF)
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Ethyl
1,6-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylate
(3m): Yield 90%; White solid; mp: 100-101 °C; IR (KBr) (νmax
,
cm-1) 3438, 2978, 1727, 1604, 1482, 1296, 1235, 1074, 852, 810
1
cm-1; H NMR (400 MHz, CD3Cl): δ 8.14 (1H, br), 7.50-7.48 (1H,
m), 7.40-7.39 (1H, m), 6.60 (1H, s), 4.43-4.37 (2H, q, J = 8.0 Hz),
3.78 (3H, s), 2.42 (3H, s), 1.40-1.36 (3H, t, J = 8.0 Hz); 13C NMR
(100 MHz, CD3Cl): δ 178.0, 163.7, 143.7, 139.9, 134.6, 134.2,
126.9, 125.9, 116.0, 112.0, 62.9, 37.2, 20.8, 14.0; HRMS (ESI-
TOF) m/z Calcd for C14H15NO3 [M+Na]+ 268.0950, found
268.0944..
Ethyl 1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (3q):
Yield 97%; White solid; mp: 98-99 °C; IR (KBr) (νmax, cm-1)
3440, 2977, 1732, 1651, 1470, 1381, 1315, 1241, 1142, 1094,
1027, 854, 764 cm-1; 1H NMR (400 MHz, CD3Cl): δ 8.42-8.39
(1H, m), 7.74-7.72 (1H, m), 7.66-7.62 (1H, m), 7.37-7.33 (1H, m),
4.68-4.63 (1H, q, J = 8.0 Hz), 4.45-4.39 (2H, q, J = 8.0 Hz), 1.73-
1.71 (6H, d, J= 8.0 Hz), 1.42-1.39 (3H, t, J = 7.2 Hz); 13C NMR
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127.0, 123.8, 118.5, 117.8, 112.2, 62.8, 55.9, 21.6, 14.0; HRMS
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